Abstract:

Many D2d-symmetric 2,2',6,6'-tetrasubstituted biphenyls are
readily prepared via net oxidative dimerization of appropriate
1,3-disubstituted benzenes. Conversion of such proprochiral
compounds to useful C2-symmetric chiral biphenyls requires
formal replacement of two substituents on opposing aryl ring
units with alternate groups. This under exploited
desymmetrization tactic has been demonstrated for the
generation of scalemic biaryls using stoichiometric chiral reagent
control, but no reports concerning its realization by a
(potentially) more efficient asymmetric catalytic approach have
appeared. Accordingly, two different possible strategies for
achieving a catalytic enantioselective biaryl synthesis based on
D2d to C2 desymmetrization were investigated: (a) enzyme
catalyzed hydrolysis of tetraester derivatives of 2,2'-biresorcinol,
and (b) transition metal catalyzed substitution from 2,2',6,6'-
tetrabromobiphenyl. In pursuit of the first approach, 2,2'-
biresorcinol was prepared from 1,3-dimethoxybenzene via nbutyllithium
initiated ortho-directed lithiation, followed by
iron(III) chloride mediated oxidative coupling of the aryllithium,
and then (in a separate step) demethylation of the resulting
2,2',6,6'-tetramethoxybiphenyl with excess boron tribromide.
Tetraacetate and tetravalerate esters of 2,2'-biresorcinol were
subsequently synthesized and their hydrolysis with the following
four distinct esterases was examined: Pseudomonas cepacia
lipase (PCL), porcine liver esterase (PLE), Candida antarctica
lipase B (CAL B), and bovine pancreas acetone powder (a source
of bovine cholesterol esterase). Turn-over was not observed in
any case; however, a majority of the enzymes studied
successfully hydrolyzed model test substrates such as phenyl
valerate, phenyl acetate, and mono- and diesters of resorcinol.
For the second approach, a significant new one-pot synthesis of
2,2',6,6'-tetrabromobiphenyl was realized from 1,3-
dibromobenzene via lithium diisopropylamide mediated ortholithiation
followed again by oxidative coupling with iron(III)
chloride (66% yield). Palladium catalyzed cross-coupling
reactions (comprising Kumada, Negishi, and Sonogashira subtypes)
were evaluated from 2,2',6,6'-tetrabromobiphenyl and 1,3-
dibromobenzene. The latter model substrate revealed that a
degree of control was possible, in that monosubstitution could be
readily achieved; however, reactions from the pivotal D2d-symmetric
2,2',6,6'-tetrasubstituted substrate typically gave either
no reaction (reflecting the high steric hindrance of the starting
material) or else complex intractable mixtures of various
polysubstituted products.